α-Synuclein is a presynaptic neuronal protein that is linked genetically and neuropathologically to Parkinson's disease (PD). α-Synuclein may contribute to PD pathogenesis in a number of ways, but it is generally thought that its aberrant soluble oligomeric conformations, termed protofibrils, are the toxic species that mediate disruption of cellular homeostasis and neuronal death, through effects on various intracellular targets, including synaptic function. Furthermore, secreted α-synuclein may exert deleterious effects on neighboring cells, including seeding of aggregation, thus possibly contributing to disease propagation. Although the extent to which α-synuclein is involved in all cases of PD is not clear, targeting the toxic functions conferred by this protein when it is dysregulated may lead to novel therapeutic strategies not only in PD, but also in other neurodegenerative conditions, termed synucleinopathies.

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α-Synuclein in Parkinson’s Disease

Mitochondria fuse and divide in response to cell demands and environment. Alterations in mitochondrial dynamics underlie various human diseases, including cancer and neurologic and cardiovascular diseases. Defining the alterations may identify potential therapeutic targets.

https://www.nejm.org/doi/suppl/10.1056/NEJMra1215233/suppl_file/nejmra1215233_appendix.pdf

Mitochondrial dynamics--mitochondrial fission and fusion in human diseases.

Summary Several biochemical abnormalities have been described in the brains of patients with Parkinson's disease (PD), including oxidative stress and mitochondrial dysfunction. The identification of specific gene mutations that cause PD has reinforced the relevance of oxidative stress and mitochondrial dysfunction in the familial and the sporadic forms of the disease. The proteins that are associated with familial PD—PTEN-induced putative kinase 1 (PINK1), DJ-1, α-synuclein, leucine-rich repeat kinase 2, and, possibly, parkin—are either mitochondrial proteins or are associated with mitochondria, and all interface with the pathways of oxidative stress and free radical damage. Insights into the aetiology and pathogenesis of PD provide hope that drugs or cocktails of drugs that might successfully intervene in the pathogenesis and slow the progression of the disease can be derived from the study of the converging rather than diverging pathways to cell dysfunction and death.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(07)70327-7.pdf

Mitochondria in the aetiology and pathogenesis of Parkinson's disease.

Intracellular α-synuclein (α-syn)-rich protein aggregates called Lewy pathology (LP) and neuronal death are commonly found in the brains of patients with clinical Parkinson disease (cPD). It is widely believed that LP appears early in the disease and spreads in synaptically coupled brain networks, driving neuronal dysfunction and death. However, post-mortem analysis of human brains and connectome-mapping studies show that the pattern of LP in cPD is not consistent with this simple model, arguing that, if LP propagates in cPD, it must be gated by cell- or region-autonomous mechanisms. Moreover, the correlation between LP and neuronal death is weak. In this Review, we briefly discuss the evidence for and against the spreading LP model, as well as evidence that cell-autonomous factors govern both α-syn pathology and neuronal death.

Selective neuronal vulnerability in Parkinson disease.

Intracellular aggregation of the human amyloid protein α-synuclein is causally linked to Parkinson’s disease. While the isolated protein is intrinsically disordered, its native structure in mammalian cells is not known. Here we use nuclear magnetic resonance (NMR) and electron paramagnetic resonance (EPR) spectroscopy to derive atomic-resolution insights into the structure and dynamics of α-synuclein in different mammalian cell types. We show that the disordered nature of monomeric α-synuclein is stably preserved in non-neuronal and neuronal cells. Under physiological cell conditions, α-synuclein is amino-terminally acetylated and adopts conformations that are more compact than when in buffer, with residues of the aggregation-prone non-amyloid-β component (NAC) region shielded from exposure to the cytoplasm, which presumably counteracts spontaneous aggregation. These results establish that different types of crowded intracellular environments do not inherently promote α-synuclein oligomerization and, more generally, that intrinsic structural disorder is sustainable in mammalian cells. Atomic resolution in-cell NMR and EPR spectroscopy show that the human amyloid protein α-synuclein remains disordered within all mammalian cells tested, including neurons, and identifies which parts of the protein dynamically interact or remain shielded from the cytoplasm, thus counteracting aggregation under physiological cell conditions. Amyloid aggregates of the protein α-synuclein are associated with Parkinson's disease and although the isolated protein is disordered in vitro, various conformations have been proposed for the protein in its physiological context in vivo, ranging from disordered monomers to folded helical tetramers. Now, using atomic-resolution in-cell NMR and EPR spectroscopy, Philipp Selenko and colleagues show that α-synuclein remains disordered within all mammalian cells tested, including neurons, and identify which parts of the protein dynamically interact with, or remain shielded from the cytoplasm, thus preventing aggregation in physiological conditions. The study presents several experimental methods applied for the first time to a protein inside mammalian cells.

/pdf/structural-disorder-of-monomeric-a-synuclein-persists-in-1qwd5xn4g9.pdf

Structural disorder of monomeric α-synuclein persists in mammalian cells

Intersecting pathways to neurodegeneration in Parkinson's disease: Effects of the pesticide rotenone on DJ-1, α-synuclein, and the ubiquitin–proteasome system

https://www.jbc.org/content/284/23/15951.full.pdf

Peroxidase Mechanism of Lipid-dependent Cross-linking of Synuclein with Cytochrome c: PROTECTION AGAINST APOPTOSIS VERSUS DELAYED OXIDATIVE STRESS IN PARKINSON DISEASE*

Hye-Mee Na

Papers

Intersecting pathways to neurodegeneration in Parkinson's disease: Effects of the pesticide rotenone on DJ-1, α-synuclein, and the ubiquitin–proteasome system

Peroxidase Mechanism of Lipid-dependent Cross-linking of Synuclein with Cytochrome c: PROTECTION AGAINST APOPTOSIS VERSUS DELAYED OXIDATIVE STRESS IN PARKINSON DISEASE*